Piperideine synthesis

In the six-membered series the alkaloids of Punica gr ana turn, isopelletier-ine and methylisopelletierine, have been obtained by treatment of enamines with acetoacetic acid. Isopelletierine (194, R = H) was prepared also by Schopf et al. from d -piperideine (309-311). The reversibility of aldol dimerization (124,131) of enamines has been established by the synthesis of methylisopelletierine (194, R = Me) from dimethyltetrahydroanabasine, accomplished by Lukes and Kovaf (101) (Scheme 19). 

The reaction of 2-(a-pyridyl)alkylmalonic acid with J -piperideine leading to formation of 3-((x-pyridyl)quinolizidine-l-carboxylic acid on decarboxylation, has been used by Van Tamelen and Foltz (316) for the syntheis of the alkaloid lupanine (Scheme 20). A very elegant synthesis of matrine has been accomplished by Bohlmann et al. (317). 

The a is L-lysine, as in the case of piperidine, but the f3 is different. The /3 is a-aminoadipic acid 6-semialdehyde. The q> is L-pipecolic acid, which is synthesized in plants from piperideine-6-carboxylic acid. In the case of many other organisms, the obligatory intermedia (q>) is derived from the /3. The

ring structure. The indolizidine nucleus will be formed only in the synthesis of the x- The deep structmal change occms when

Claisen reaction with acetyl or malonyl CoA (Cra/mCoA) and the ring closme process (by amide or imine) to 1-indolizidinone, which is the x- The second obligatory intermedia ( k ) only has the indolizidine nucleus. 

The iminium ions produced by the C- alkylation of A2-piperideines can have synthetic utility for the formation of additional carbon-carbon bonds. This concept is illustrated (Scheme 12) by the synthesis of vincamone and its epimer from piperideine (120). Treatment of enamine (120) with ethyl iodoacetate gave iminium ion (121) which cyclized to (122) under the reaction conditions. Completion of the synthesis was accomplished by base followed by acid treatment (82TL177). 

The reaction of A2-piperideine (115) with methyl vinyl ketone to give (124) is another example of how initial electrophilic attack on the enamine double bond can be used in heterocyclic synthesis (77ACR193). This overall process is an enamine analog of the Robinson annelation and is a useful approach to the perhydroquinoline ring system. 

The addition of acid to Az-piperideine results in an iminium ion that readily reacts with nucleophilic species. This reaction has been particularly useful for the formation of carbon-carbon bonds in alkaloid total synthesis. For example, key steps in the total synthesis of ( )-porantherine (equation 36) (74JA6517), coccinelidine (equation 37) (77H(7)685) and eburnamonine (equation 38) (65JA1580) were acid-catalyzed ring closures between A2-piperideine derivatives and ends. Even the weakly nucleophilic carbon-carbon double bond can participate in this type of reaction (80JA5955), as has been demonstrated by a recent total synthesis of a morphinan derivative (Scheme 13). 

Two interesting approaches for the stereospecific oxidation of the enamine bond of Az-piperideine have been reported in connection with studies on the synthesis of vinblastine derivatives (Scheme 14) (79JA2243). 

The double bond of A3-piperideines can be used to activate and control the functionalization of the six-membered ring. For example, studies on the synthesis of the benzomorphans require 2-benzyl-A3-piperideine derivatives. One approach to these compounds has been... 

The A1-piperideines, in contrast to the A2- and A3-isomers, are usually very reactive toward nucleophilic reagents. Depending upon the nature of the nucleophile, two reaction pathways are possible (equation 48). The nucleophile can add to the inline carbon or the nucleophile can abstract the a-hydrogen. Since both of the resulting anions can undergo further reactions, A1-piperideines have potential for the synthesis of complex six-membered ring heterocycles. 

The reactions shown in equations (49)-(51) are reminiscent of the Mannich reaction. An example of where this approach was used to great advantage for the synthesis of lycopodine (82JA1054) is illustrated in Scheme 35. In this sequence the A2-piperideine was not isolated but was prepared as a reactive intermediate. 

The A2-piperideines are capable of behaving as dehydrosecodine analogs in alkaloid synthesis. One of the first successful applications of this approach is provided by the total synthesis of the aspidosperma alkaloid minovine (234 Scheme 41) (73JA7146). 

A closer analogy to dehydrosecodine (228) has been developed using A2-piperideines (e.g. 236). These compounds are not isolated but are produced by the fragmentation of salt (235). This elegant method is illustrated in Scheme 42 by the synthesis of racemic pandoline (237) and its C2o epimer. This reaction has provided an efficient route to a number of aspidosperma alkaloids (80JOC3259). 

The intramolecular cycloaddition reaction of enamides has recently been exploited in alkaloid synthesis (81JOC3763). Application of A2-piperideine derivatives resulted in the... 

The Diels-Alder reaction using the double bond of a A -piperideine as the dienophile is relatively rare. The potential of this reaction is illustrated by the synthesis of lupinine (242) <79H(12)949), where the quinolizidine ring was formally constructed by a Diels-Alder reaction involving A1-piperideine and the ester (240 Scheme 43). 

If the amino group forms part of the ketone, as it does with y-87, 88 and 8-amino-ketones,89,90 heterocyclic enamines are obtained. 1,2-Dialkyl-J2-pyrrolines and 1,2-dialkyl-J2-piperideines (15) are formed from secondary amino groups, whereas primary amino groups 91 lead to 2-alkyl-J pyrrolines and 2-alkyl-J -piperideines. Gabriel90 used the suitably substituted phthalimidoketone for the synthesis of the alkaloid y-coniceine (15 R = H, R = n-Pr, n = 2). 

In some cases, this synthesis may be simplified by omission of isolation at the oxazine stage. Thus, l-methyl-4-phenyl-3-piperideine (15) R = Me, R = H) may be obtained directly in 52% yield by heating... 

Some substituted 3-piperideines are accessible via the Mannich synthesis. Thus, refluxing a mixture of formaldehyde, acetone, and the hydrochloride of the Mannich base previously prepared from formaldehyde, isobutyraldehyde, and methylamine hydrochloride affords l,5,5-trimethyl-3-acetyl-3-piperideine (34).27... 

The methylenebiscarbamate reaction of 1,3-dienes was used in the synthesis of the alkaloid anatabine (see Section V,B) and 4-methyl-3-piperideine, an intermediate in the synthesis of the pharmaceutical Lerone (see Section VI). 

Some l-alkyl-2-benzyl-3-piperideines (185) were used in the Grewe synthesis of the benzomorphane-like analgesics (186). The ring closure between the ortho position of the benzyl residue and position 4 of the 3-piperideine nucleus was usually accomplished by heating in 48% hydrobromic acid or 85% phosphoric acid.41,103,188-193... 

Pyrrolines X -piperideines. A convenient, general synthesis of A -pyrroIincs is based on the reduction of suitable nitriles with DIBAH (equation 1). 

The well-known piperidine alkaloid anabasine, found in Anabasis aphylla L. (Chenopodiaceae) and Nicotiana glauca Graeb. (Solanaceae), is thought to be synthesized in plants through dimerization of A1-piperideine (followed by oxidation).243 A terpyridine nicotelline (173) was found in tobacco leaf,244andits structure was proved by synthesis.245... 

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